EL INFORME DE LA INSPECCIÓN DE TRABAJO Y SEGURIDAD SOCIAL

IFNs are important chemical mediators of innate immunity and elicit distinct antiviral responses. They are grouped into three classes called type I, II and III IFNs, according to their amino acid sequence (442). In humans, type I IFNs comprise of multiple IFNα subtypes, one IFNβ gene and other genes of less well-defined roles such as IFN-ω, IFN-ε, IFN-τ, IFN-δ and IFN-κ, while IFNγ is the only member of type II IFN. IFNα/β are the major type I interferons secreted by cells in response to infectious agents, particularly viral pathogens. They have several major functions during infection. They are known to induce an antimicrobial state in

neighbouring and infected cells via the induction of interferon stimulated genes (ISGs), modulate the innate immune response in a balanced manner and activate the adaptive immune system by

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promoting antibody production and effector T cell responses (32). The Type III IFN gene family consists of three genes IFN-λ1, λ2and λ3 and is more closely related in structure and sequence to the cytokine IL-10 (117).

Type I IFNs can be produced by almost any type of cell in the body in response to stimulation, whereas haematopoietic cells, particularly pDCs specialize in its secretion (512). The first step in the production of type I IFNs is the recognition of microbial pathogens by cellular PRRs. Several PRRs including RLRs, TLRs and NLRs sense different microbial components as described previously. Pathogen sensing by the PRRs initiates a signalling

cascade, which culminates in the activation of transcription factors IRF-3, IRF-7 and NFκB. The transcription factors then translocate to the nucleus, bind to the IFN gene promoter and induce transcription of the IFN gene. IRF3 and IRF7 are phosphorylated by cellular kinases and

translocate to the nucleus after dimerization (262), whereas the IKK complex, consisting of IKK- α, IKK-β and IKK-γ, phosphorylates the NFκB inhibitor IκB leading to its proteasome-

dependent degradation and release of functional NFκB to translocate to the nucleus (251). The type I IFNs can also be induced by host factors and cytokines such as TNF, which signals via IRF1 rather than through IRF3 and IRF7 (592). IFN-α/β exerts the antiviral effect in

neighbouring and infected cells by binding and signalling through a heterodimeric

transmembrane receptor termed the IFNα receptor (IFNAR), which is composed of two subunits IFNAR1 and IFNAR2. Type I IFN binding to IFNAR activates the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and Tyrosine kinase 2 (TYK2), which then phosphorylate the transcription factors signal transducer and activator of transcription 1 and 2 (STAT1 and STAT2) (27, 113). Phosphorylated STAT1 and STAT2 dimerize and translocate to the nucleus, where they assemble with IRF9 to form a trimolecular complex called IFN-stimulated gene

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Figure 1.5 Receptors of type I, II and III IFNs. Distinct receptors are used by the three classes of IFNs.

Type I IFNs signal through IFNα receptor (IFNAR), a heterodimer comprised of subunits IFNAR1 and IFNAR2. Type II IFNs signal through IFNγ receptor (IFNGR) comprised of subunits IFNGR1 and IFNGR2. Type III IFNs signal through IFNλ receptor (IFNLR), a heterodimer comprised of IL10Rβ and IFNLR1 subunits. Binding of the IFNs to their respective receptors trigger phosphorylation of the JAK and TYK kinases, which in turn phosphorylate the receptors at specific tyrosine residues leading to recruitment of STAT proteins and their phosphorylation. The STAT proteins dimerize and recruit other transcription factors to form a complex, which translocates to the nucleus and triggers transcription of genes regulated by IFN stimulated response elements (ISRE) and gamma-activated sequence (GAS) promoter sequences.

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factor 3 (ISGF3). ISGF3 binds to DNA sequences known as IFN-stimulated response element (ISREs), activating the transcription of ISGs (Fig. 1.5) (468). The ISGs are primarily responsible for the antiviral effects of type I IFNs.

IFN-gamma (IFNγ) is the lone type II IFN and is known to be induced by many cell types such as macrophages, DCs, NK cells, NKT cells, CD4+ T cells, CD8+ T cells and B lymphocytes (371). The production of IFNγ is controlled by the cytokines IL-12 and IL-18, which are secreted by the APCs in response to infection (470). Even though IFNγ production is largely restricted to immune cells, IFNγ receptors (IFNGR) comprised of IFNGR1 and IFNGR2 chains are expressed by most cell types and hence are capable of responding to IFNγ (546). The IFNGR is made up of two ligand-binding IFNGR1 chains associated with two IFNGR2 chains that is involved in signal transduction (548). Upon IFNγ binding to IFNGR, kinases JAK1 and JAK2 bind to IFNGR1 and IFNGR2 subunits respectively and become tyrosine phosphorylated (371). Activated JAKs phosphorylate the IFNGR tails, which recruit the STAT1 monomers, which are again phosphorylated by the JAKs leading to STAT1 dissociation from the receptors and STAT1 homodimerization (371). The STAT1 homodimer translocates to the nucleus, binds to γ- activated sequence (GAS) elements to induce transcription of IFNγ responsive genes (Fig. 1.5) (371). Many of the transcribed genes are transcription factors and the major one is interferon response factor 1 (IRF1) (55). IFNγ secretion has many different immunomodulatory effects. It is involved in the upregulation of MHC-I molecules and in increasing the quality, quantity and repertoire of peptides loaded onto MHC-I (371). Other functions of IFNγ include upregulation of MHC-II molecules for efficient antigen presentation, development of a Th1 response and the activation of the microbicidal functions of macrophages (371). Type I and type II IFN are known

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to induce the expression of a common set of ISGs as well as a distinct set of ISGs in order to exert its antiviral and immunomodulatory functions (331).

Type III IFNs or IFNλ consists of four proteins IFNλ1 (IL-29), λ2 (IL-28A), λ3 (IL-28B) and λ4. In contrast to type I IFNs, IFNλ was fairly recently discovered and shares many

biological functions with type I IFN (288, 483). IFNλ expression is induced by the stimulation of the same PRRs that induce type I IFN expression, with one difference being the Ku70 DNA sensor that activates IFNλ but not the type I IFNs (305, 606). The IFNλ receptor (IFNLR) is a unique heterodimeric receptor which shares one subunit with the IL-10 family of cytokines called IL10Rβ and a second subunit specific to IFNλ called IFNLR1 or IL28Rα (Fig. 1.5) (288, 483). In contrast to IFNAR which is expressed by almost all cell-types, IFNLR expression is restricted to epithelial cells and hepatocytes and because of this, IFNλ provides the therapeutic benefits of type I IFN and yet avoid the side-effects that come with type I IFN treatment (305). In terms of the transcription factors that induce IFNλ expression, it has been reported that IRF and NFκB can induce IFNλ expression independently, which is different from the concerted action of several transcription factors required for type I IFN induction (536). The IFNLR signals through a similar JAK-STAT pathway as the IFNAR complex and induces a subset of the same ISGs (467). However the magnitude of IFNλ stimulated response is generally lower than type I IFNs and lasts for a longer duration with a delayed peak response (357).